1. The Field of the Invention
The present invention is related to methods and compounds for use in the field of determining renal function by means of scintigraphic urography. More particularly, the present invention is directed to renal system imaging in which technetium-99m radiolabeled chelates are used.
2. The Prior Art
Regulation of the content and quantity of body fluids is critical to the basic physiology of bodily functions. For instance, it is necessary for the body to regulate such fluid-related variables as total body fluid volume, constituents of extracellular body fluids, the acid-base balance in body fluids, and various factors that affect interchange of extracellular and intracellular fluids (most notably, factors that affect the osmotic relationship between such fluids).
The kidneys are the primary body organs that are responsible for regulation of the composition of body fluids. Thus, the kidneys maintain body fluids within a physiologically acceptable range by excreting most of the end products of metabolism and by regulating the concentrations of desirable body fluid constituents.
The human body contains two kidneys that function to form urine containing fluid constituents that are to be eliminated through the bladder. The basic biological unit that performs the work of the kidney is the "nephron." Each kidney is comprised of some one million nephrons, with each nephron being capable of regulating body fluid independently of other nephrons.
The kidneys function on body fluid by filtering a substantial volume of blood (about one-fifth of the total cardiac output is pumped directly to the kidneys); this specific volume of blood is known as the "renal fraction." Blood flow through the kidneys of a typical adult male averages about 1.2 liters per minute. As the blood passes through the kidneys, the nephrons "clear" the blood plasma of unwanted substances--for example, the metabolic end products (such as urea, creatinine, uric acid, sulfates and phenols) and the nonmetabolic ionic substances (such as excess sodium, potassium, and chloride).
The nephrons are basically comprised of a capillary bed termed the "glomerulus," a second capillary bed known as the "peritubular" capillaries, and a urine-forming component known as the "tubule." The tubule is separated from the glomerulus by a membrane known as the "glomerular membrane." As the renal fraction of blood flows through the glomerulus, the glomerular membrane passes a small proportion. (generally no more than 20%-25%) of the plasma comprising the renal fraction into the tubule. This filtered fluid then flows through the tubule, and towards the pelvis of the kidney, which in turn feeds into the bladder. As fluids flows through the tubule, most of the water and much of the electrolytes and other "wanted" substances are reabsorbed and returned to the blood; the "unwanted" substances (such as metabolic end products and excess water and electrolytes) pass into the bladder for elimination as urine.
The remaining portion of the renal fraction that does not cross the glomerular membrane exits the glomerulus and then enters the peritubular capillaries; from there, a portion of the renal fraction is generally returned to the venous system. The large quantities of fluid components reabsorbed in the tubules are also transported to the peritubular capillaries by diffusion through the tubular membrane.
While large quantities of fluid diffuse from the tubule into the peritubular capillaries for return to the vascular system, diffusion of some plasma components occurs in the reverse direction--from the peritubular capillaries to the tubules. For instance, sodium ions are actively transported across the tubular membrane and into the peritubular fluid, thereby conserving this important electrolyte. However, this creates a substantial negative charge within the tubule with respect to the peritubular fluid. In the proximal tubule, this electrical difference is approximately 20 millivolts, and can climb to as much as 120 millivolts in the distal tubule.
This difference in electrical potential potentiates diffusion of some positive ions, most notably potassium, from the peritubular fluid into the tubule. This flow of potassium into the tubules across the tubular membrane due to the electronegativity gradient is termed "passive secretion."
In addition to this passive secretion, some ionic materials are "actively" secreted into the tubules. For instance, para-aminohippuric acid (generally referred to as "PAH") is actively secreted from the peritubular fluid into the tubules; although only about twenty percent (20%) of the renal fraction passes into the tubules as glomerular filtrate, nearly ninety percent (90%) of any PAH in the blood is removed by the kidneys. Thus, approximately seventy percent (70%) of the PAH is removed from the plasma by active secretion into the tubules.
Occasionally, a kidney will become damaged and thus diminish or even cease its function of clearing the blood. Various renal function tests have been devised to assist a physician to evaluate the extent and type of kidney damage that has occurred. Also, these renal function tests are useful in evaluating whether a kidney is operating properly following a kidney transplant operation.
One such renal function testing procedure is known as intravenous scintigraphic urography (this procedure is also commonly known as a dynamic renal function imaging study). This procedure has historically involved the intravenous administration of a radioactively labeled iodine substance, such as I-131 ortho-iodohippurate (often referred to as "I-131 OIH"). Like PAH, I-131 OIH is rapidly removed from the blood by active tubular secretion in addition to glomerular filtration, thereby causing significant quantities of radiolabeled material to concentrate in the kidneys within a few minutes after administration. Images can be obtained using gamma scintillation cameras capable of showing the location of this radiolabeled material, and thereby giving a useful indication of the quality of renal function in the kidneys.
Despite the fact that I-131 OIH is an important tool in evaluating renal function, it suffers from some significant drawbacks. First, because of the high-energy gamma radiation output (364 KeV) of iodine-131 ("I-131"), the use of I-131 OIH results in images having poor spatial resolution. This makes it difficult to observe fine detail within the kidneys, and thereby limits the amount of useful information which is obtainable by this method.
Further, the renal extraction efficiency (the ability to clear the radiopharmaceutical from blood passing through the kidneys) of I-131 OIH is only about 65%-80%, and, while this is quite good, a higher extraction efficiency would result in higher kidney-to-background ratios, which facilitate detection of minimal renal function. In addition, I-131 emits a beta particle during radioactive decay which can cause damage to surrounding tissue. Further, because free radioiodine that accompanies I-131 OIH is readily taken up by the patient's thyroid gland, the maximum dose of I-131 OIH must generally be held to about 200 to 300 microcuries. This low dosage requires a significant exposure period when taking the radioactive image, which in turn decreases the temporal resolution of sequential images taken during renal function studies.
In order to improve upon the resolution obtainable in a radioactive renal function procedure, alternative radiolabeled materials have been earnestly sought. It is currently believed that the most desirable radioactive label is technetium-99m ("Tc-99m"), which has significantly improved resolution properties when compared to the I-131 label, because Tc-99m emits a lower energy (140 KeV) radiation. This lower energy radiation is well-suited for use in connection with standard radiation-measuring instrumentation. The radiation dose per millicurie is much less for Tc-99m than is the case when using I-131; this is because Tc-99m has a half-life of only about six (6) hours (as opposed to a half-life of eight (8) days for I-131), and also because Tc-99m does not emit beta particles during its decay process.
The radioactive properties of Tc-99m result from the transition of the metastable excited nucleus to ground state Tc-99. The resulting Tc-99 has such a long half-life (200,000 years) as to be virtually innocuous. As a result, dosages of as much as 30,000 microcuries of Tc-99m may be administered without danger to the patient. The result is that much shorter exposure periods are required than when I-131 OIH is used. This in turn makes it possible to take acceptable perfusion images during the first pass of radiopharmaceutical through the kidneys.
The foregoing properties of Tc-99m make it ideal as a tool in nuclear medicine, since it is well-suited for use with standard instrumentation, and because it subjects the patient with whom it is used to a relatively low dose of radiation.
Because of the demonstrated advantages of the Tc-99m label over the I-131 label, a great deal of effort has gone into developing a Tc-99m compound having a high renal extraction efficiency. A number of Tc-99m-labeled chelates have been reported in the literature.
One Tc-99m-labeled compound, Tc-99m diethylenetriaminepentaacetic acid (generally referred to as "Tc-99m-DTPA") has sometimes been used in radioactive renal function evaluation procedures because of its excellent imaging characteristics. However, Tc-99m-DTPA is not actively secreted into the tubules of the kidney, and thus has a maximum extraction efficiency of only about 20-25%; this would be expected in connection with a substance entering the tubules only as a result of glomerular filtration. This lower extraction efficiency makes the use of Tc-99m-DTPA less sensitive in detecting mild renal disease than is I-131 OIH. Even so, because of the ability of Tc-99m-DTPA to provide perfusion images of the renal blood supply to the kidneys during the first pass after injection, it is common to use Tc-99m-DTPA together with I-131 OIH.
Another Tc-99m compound reported in the literature is Tc-99m-N,N'-bis(mercaptoacetyl)-ethylenediamine. ("Tc-99m-DADS"). While this compound has been found to be secreted in the tubules, the tubular extraction efficiency of Tc-99M-DADS is only about 53% in normal patients, and even less in patients having decreased renal function. This very low extraction efficiency makes this compound unsuitable as a replacement for I-131 OIH.
Although Tc-99m-DADS is itself deemed unsatisfactory as a replacement for I-131 OIH, the fact that it is actively secreted by the tubules led to experimentation with various analogs. For instance, various methyl, hydroxymethylene, benzo, carboxylate, dicarboxylate, and benzocarboxylate analogs have been synthesized and tested.
Of these, the most efficiently excreted analog has been Tc-99m-N,N'-bis(mercaptoacetyl)-2,3-diaminopropanoate (Tc-99mCO.sub.2 -DADS). Unfortunately, this ligand exists as two stereoisomeric products upon chelation, referred to as Tc-99m-CO.sub.2 -DADS-A and Tc-99m-CO.sub.2 -DADS-B. Further, the Tc-99m-CO.sub.2 -DADS-B isomer was found to be far less efficiently removed by the kidneys than was the Tc-99m-CO.sub.2 -DADS-A isomer. Because of the inherent difficulty in separating these two isomers for clinical use, commercial development of Tc-99m-CO.sub.2 -DADS-A has proven to be impractical.
From the foregoing, it will be appreciated that it would be a substantial improvement in the field of renal function imaging if a Tc-99m compound could be provided that has a relatively high extraction efficiency, yet does not exhibit other adverse properties that would make it unsuitable as a replacement for I-131 OIH. Because of the short half-life of Tc-99m, it would also be a significant advancement if such Tc-99m imaging compounds could be easily prepared immediately prior to conducting a renal function diagnostic procedure. Such Tc-99m compounds and methods are disclosed and claimed herein.